Anti-plaque compositions comprising a combination of morpholinoamino alcohol and chelating agent

ABSTRACT

Compositions having improved anti-plaque activity comprise a synergistic combination of a) a morpholinoamino alcohol, such as 3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine, and b) a chelating agent such as ethylenediaminetetraacetic acid.

BACKGROUND OF THE INVENTION AND INFORMATION DISCLOSURE

Bacterial aggregation on the teeth known as plaque has been identifiedas a cause of dental caries, gingivitis, periodontitis and other gumdiseases Mechanical methods have been used for some time for theprevention of dental plaque but have not generally achieved sufficientresults. Studies have shown that mechanical methods such as the use ofdental floss and interspace brushes do not eliminate interproximalplaque. During the past decade or more chemical plaque control as asubstitute or supplement to mechanical methods has been tried.

Octapinol has been tested for its ability to reduce plaque formation andthe development of gingivitis by Willard, Edwardsson, Attstom andMatsson, "The effect of Octapinol on dento-gingival plaque anddevelopment of gingivitis", Journal of Periodontal Research, Volume18,pages 429-437, (1983). Here it is reported that octapinol may preventthe development of plaque. Some adverse side effects of octapinol areits toxicity lasting bitter taste and its brownish staining of theteeth.

U.S. Pat. No. 4,636,382 describes morpholino compounds which are usefulfor the inhibition or removal of dental plaque. The '382 patent alsodiscloses that a wide variety of chemical and biological agents havebeen suggested for the inhibition of plaque, such as penicillin,chlorohexidine, 8-hydroxyquinoline and ethylenediamine tetraacetate.However, many of these chemical and biological agents are described asexhibiting insignificant effects and often causing serious side effects.The morpholino compounds of the '382 patent are described as having alow antibacterial effect and lacking undesirable side effects such asdiscoloration of the teeth.

U.S. Pat. No. 4,610,871 describes the use of monoalkyl or dialkyl ethersof dianhydrohexitols to inhibit the formation of plaque and calculus onteeth. U.S. Pat. No. 4,178,363 describes the use of n-undecylenic acidor a calcium or zinc salt thereof for reducing dental plaque andinfections of the teeth and gums. U.S. Pat. No. 4,119,711 describesspiro 1-(hydroxyalkyl)-piperidino derivatives which have efficacy inreducing the formation of plaque. U.S. Pat. No. 3,976,765 describesbis-biguanido hexanes in combination with nonionic surfactants andcertain foam stabilizers for use in a variety of oral preparations.

Additionally, U.S. Pat. No. 3,887,712 discloses that alexidinedihydrofluoride is useful in the treatment of dental plaque, calculus,gingivitis and related periodontal diseases. U.S. Pat. No. 4,160,821discloses that a glycerine solution of zinc chloride or other acceptablezinc salts provides effective therapy for gingivitis when applied to thegingivae and teeth.

Efforts continue toward finding improved means for reducing and/oreliminating plaque without many of the side effects associated with theprior art, such as discoloration of teeth or tongue, desquamation andsoreness of oral mucosa, objectionable taste, toxicity and imbalance ofthe oral flora. It is an object of the present invention to providenovel compositions which are useful in the treatment of plaque andgingivitis without many of the adverse side effects associated withprior art compositions. It is another object of this invention toprovide anti-plaque compositions which would cause little or noecological imbalance of the oral flora. It is a further object of thisinvention to provide compositions comprising a combination of amorpholinoamino alcohol and a chelating agent wherein these compositionspossess synergistically improved anti-plaque and anti-gingivitisactivity.

SUMMARY OF THE INVENTION

The present invention relates to novel compositions comprising asynergistic combination of one or more morpholinoamino alcohols orpharmaceutically-acceptable salt thereof and one or more chelatingagents. The morpholinoamino alcohol has the chemical formula ##STR1##wherein R₁ is a straight or branched alkyl group containing 8 to 16carbon atoms at the 2- or 3- position of the morpholino ring, and R₂ isa straight or branched alkyl group containing 2 to 10 carbon atomsterminating with a hydroxy group. The chelatings agents include, forexample, ethylenediaminetetraacetic acid, edetate sodium, edefatedisodium, edetate calcium disodium, edetate trisodium, deferoxamine,ditio carb sodium, penicillamine, pentetic acid, succimer, trientine andthe like.

The preferred morpholinoamino alcohol is3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine and the preferredchelating agents are ethylenediaminetetraacetic acid and its calcium andsodium salts. The compositions preferably comprise about 0.005-5% byweight of the morpholinoamino alcohol and about 0.33% by weight of thechelating agent. The compositions of this invention are useful in a widevariety of formulations, such as, for example, toothpaste, mouthwash,chewing gums and other dentifrices to reduce plaque or gingivitis. Thesecompositions have synergistically improved anti-plaque andanti-gingivitis activity with less side effects.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a transmission electron micrograph (136,000×magnification) ofFusobacterium nucleatum (ATCC # 10953) treated with 0.1Mphosphate-buffered saline solution at pH 7.0. Outer membrane (OM),periplasmic space (PS), peptidoglycan layer (R) and cytoplasmic membrane(CM) are clearly shown.

FIG. 2 is a transmission electron micrograph (136,000×magnification) ofFusobacterium nucleatum treated with 0.2%3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine hydrochloride for 30minutes at 37° C. FIG. 2 shows bacteria cells with some surface blebs(B). The blebs (B) possess outer membrane surfaces similar to those onthe bacteria cells. Electron dense intracellular matrix is seen in thesetreated bacteria.

FIG. 3 is a transmission electron micrograph (136,000×magnification) ofFusobacterium nucleatum treated with 0.2%3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine hydrochloride and 0.1%ethylenediaminetetraacetic acid for 30 minutes at 37° C. A greatlyincreased number of surface blebs (B) are evident as extensions of theouter membrance. The inner cytoplasmic membrane (CM) is discontinuouslyruptured and the periplusmic space (PS) is expanded. An absence of thepeptidoglycon layer was noted.

DETAILED DISCUSSION

This invention involves novel compositions which have improvedanti-plaque or anti-gingivitis activity. The novel compositions of thepresent invention comprise a synergistic combination of apharmaceutically effective amount of a) one or more morpholinoaminoalcohol(s) or pharmaceutically-acceptable salt thereof and b) one ormore chelating agent(s).

The morpholinoamino alcohols useful according to this invention have thechemical formula ##STR2## wherein R₁ is a straight or branched alkylgroup containing 8 to 16 carbon atoms at the 2- or 3-position of themorpholino ring, and R₂ is a straight or branched alkyl group containing2 to 10 carbon atoms terminating with hydroxy group. Preferably, the sumof the carbon atoms in said groups R₁ and R₂ ranges from 10 to 20, morepreferably from 12 to 16. The morpholinoamino alcohols of this inventionare described in U.S. Pat. No. 4,636,382; the disclosure of which isherein incorporated by reference.

The morpholinoamino alcohols can be prepared by several processes asdescribed in U.S. Pat. No. 4,636,382, such as (a) by alkylating amorpholino derivative having the formula ##STR3## wherein R₁ is asdefined above; with an alkylating agent of the formula

    R.sub.2 X

wherein R₂ is as defined above and X is halogen or an organic sulfonicester, or wherein X together with a hydroxyl group present in R₂ is areactive oxide; (b) by ring closure of a compound having the generalformula ##STR4## wherein R₁ is as defined above, X is halogen or anorganic sulfonic ester and A represents CH₂ groups, one CH₂ group beingsubstituted with the group R₁ ; with an amino alkanol of the generalformula

    NH.sub.2 R.sub.2

wherein R₂ is as defined above: (c) by reducing a mono- or di-oxosubstituted morpholine having the general formula ##STR5## wherein R₂ isas defined above, n is 0 or 1, and R₁ is as defined above and is at the2-position when n is 1 and at the 2- or 3-position when n is O, or (d)by starting from a morpholino compound having the general formula##STR6## wherein R₁ is as defined above and R₃ is a straight or branchedalkyl group containing a group transformable to OH or CH₂ OH.

The most preferred morpholinoamino alcohol for use in this invention is3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine represented by thechemical formula ##STR7## Also most preferred is the hydrochloride saltof 3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine. This compound is awhite, odorless, crystalline powder which is very soluble in water,alcohols and chloroform and has a melting point of about 70° C.

The morpholinoamino alcohols of this invention can be used in their freebase form or as pharmaceutically - acceptable salts thereof. Someexamples of pharmaceutically - acceptable salts are the salts of acidssuch as acetic acid, phosphoric acid, boric acid, hydrochloric acid,maleic acid, benzoic acid, citric acid, malic acid, oxalic acid,tartaric acid, succinic acid, glutaric acid, gentisic acid, valericacid, gallic acid, beta- resorcylic acid, acetyl salicylic acid,salicylic acid, perchloric acid, barbituric acid, sulfanilic acid,phytic acid, p-nitro benzoic acid, stearic acid, palmitic acid, oleicacid, myristic acid, lauric acid and the like. The most preferred saltsare those of hydrochloric acid.

As the morpholinoamino alcohols of this invention by themselves haveonly weak anti-microbial activity, it is critical to the practice ofthis invention that said morpholinoamino alcohols be present incombination with one or more chelating agent(s). It is the synergisticcombination of said morpholinoamino alcohol and a chelating agent whichprovides the compositions of this invention with their improvedanti-plaque and anti-gingivitis properties. Without being bound by anytheory or mechanism of action, it is believed that these morpholinoaminoalcohols inhibit key bacterial membrane functions such as carbohydrateuptake, cellular permeability, cell metabolism and cell division.Bacterial cells which are weakened by these morpholinoamino alcohols aremore effectively eradicated by chelating agents. Thus, compositions ofthis invention comprising a combination of said morpholinoamino alcoholsand chelating agents are extremely effective in inhibiting plaqueformation and reducing preformed plaque and for treating gingivitis.These compositions have also demonstrated effectiveness in inhibitingacid production by bacteria such as Streptococcus mutans, and thereforethese compositions would have anti-caries activity in example 2.

Moreover, studies show a very low order of acute and subacute toxicity,no mutagenic activity, no adverse effect on reproduction and no stainingof teeth by the morpholinoamino alcohols of the present invention.

Chelating agents useful according to this invention are well known inthe art as ligand-containing compounds which form coordination compoundsin which a central metal ion is attached by two or more coordinatelinks. Chelating agent as used herein includes both the uncomplexed andmetal-complexed forms of the ligand-containing compounds. Preferredchelating agents are ethylenediaminetetraacetic acid (EDTA) and itscalcium and sodium salts (such as edetate sodium, edetate disodium,editate calcium disodium and edetate trisodium), deferoxamine, ditiocarbsodium, penicillamine, pentetic acid, succimer, trientine aluminumsalts, citric acid-sodium salt, gluconic acid-sodium salt, tartaricacid, sodium hexametaphosphate, sodium acid pyrophosphate, sodiumtripolyphosphate, anthranilic acid, phosphonate, polyacrylic acid,alkyl-diamine polyacetic acids and salts thereof and the like. The mostpreferred chelating agents for use in this invention are EDTA and itscalcium and sodium salts.

In the compositions of the present invention, the morpholinoaminoalcohols are present preferably in an amount ranging from about 0.005%to about 5.0% by total weight of said composition; more preferably fromabout 0.01% to about 1.0%; and most preferably from about 0.05% to about0.2%. The amount of said chelating agents in the compositions preferablyranges from about 0.03% to about 0.50% by total weight of saidcompositions; more preferably from about 0.17% to about 0.40%; and mostpreferably from about 0.30% to about 0.35%.

The essence of the present invention is the synergistic effect ofinhibiting and reducing the growth of plaque bacteria, which is achievedwhen the morpholinoamino alcohols and the chelating agents are utilizedin combination in effective concentrations in the oral cavity. Thecombined effects of the morpholinoamino alcohol,3-(4-propylheptyl)-4(2-hydroxyethyl) morpholine, with a chelating agent(disodium EDTA) are demonstrated in FIGS. 1-3 and Example 11.Smallerquantities of each of these components are required to obtain effectiveinhibition of plaque and other bacteria than if each component wasutilized alone. Since lower quantities of each component can be used inthe compositions of this invention, the side effects associated witheach of the components would be correspondingly reduced or eliminated.

In one form of this invention, the composition may be a liquid such as amouthwash or rinse. In such a composition the vehicle is typically awater-alcohol mixture. Generally the ratio of water to alcohol is in therange of from about 1:1 to about 20:1, preferably about 3:1 to about20:1 and most preferably about 3:1 to about 10:1 by weight. The mostpreferred mouthwash or mouthrinse compositions comprise from 0 to about30% by weight of alcohol such as ethanol. The total amount ofwater-alcohol mixture in a mouthwash composition is typically in therange from about 70% to about 99.9% by weight of the composition. The pHvalue of such mouthwash compositions is generally from about 4.0 toabout 7.0 and preferably from about 5 to about 6.5. A pH below 4 wouldbe irritating to the oral cavity. A pH greater than 7 would result in anunpleasant mouth feel.

Oral liquid compositions may also contain surface active agents inamounts up to about 5% and fluorine-providing compounds in amounts up toabout 2% by weight of the composition.

Surface active agents are organic materials which afford completedispersion of the composition throughout the oral cavity. The organicsurface active material may be anionic, non-ionic, amphoteric, orcationic. Suitable anionic surfactants are water-soluble salts of higherfatty acid monoglyceride monosulfates, such as the sodium salt of themonosulfated monoglyceride of hydrogenated coconut oil fatty acids;higher alkyl sulfates, such as sodium lauryl sulfate; alkyl arylsulfonates, such as sodium dodecyl benzene sulfonate; higher alkylsulfonacetates; higher fatty acid esters of 1,2-dihydroxy propanesulfonates; and substantially saturated higher aliphatic acyl amides oflower aliphatic amino carboxylic acids such as those having 12 to 16carbons at the fatty acid, alkyl or acyl radicals.

Non-ionic surface active agents include condensates of sorbitanmono-oleate with from 20 to 60 moles of ethylene oxide (e.g., "Tweens" atrademark of ICI United States, Inc.), condensates of ethylene oxidewith propylene oxide and condensates of propylene glycol ("Pluronics" atrademark of BASF-Wyandotte Corp.).

Amphoteric surfactants useful in the present invention are zwitterionshaving the capacity to act as either an acid or a base. They aregenerally non-irritating and non-staining. Non-limitative examples ofsuitable amphoteric surfactants include cocoamidopropyldimethyl sultaineand cocodimethylbetaine (commercially available from Lonza Chemical Co.under the tradenames Lonzaine CS and Lonzaine 12C, respectively).

Cationic surface active agents are molecules that carry a positivecharge, such as the quaternary ammonium compounds.

Other suitable non-ionic surfactants are the condensation products of analpha-olefin oxide containing 10 to 20 carbon atoms, a polyhydricalcohol containing 2 to 10 carbons and 2 to 6 hydroxyl groups and eitherethylene oxide or a heteric mixture of ethylene oxide and propyleneoxide. The resultant surfactants are heteric polymers having a molecularweight in the range of about 400 to about 1600 and containing 40% to 80%by weight of ethylene oxide, with a alpha-olefin oxide to polyhydricalcohol mole ratio in the range of about 1:1 to 1:3.

A fluorine providing compound may be present in the oral compositions ofthis invention. These compounds may be slightly water soluble or may befully water soluble and are characterized by their ability to releasefluoride ions or fluoride containing ions in water. Typical fluorineproviding compounds are inorganic fluoride salts such as soluble alkalimetal, alkaline earth metal, and heavy metal salts, for example, sodiumfluoride, potassium fluoride, ammonium fluoride, cuprous fluoride, zincfluoride, stannic fluoride, stannous fluoride, barium fluoride, sodiumfluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodiummonofluorophosphate, aluminium mono-and difluorophosphate andfluorinated sodium calcium pyrophosphate.

In a oral liquid composition such as a mouthwash, the fluorine providingcompound is generally present in an amount sufficient to release up toabout 0.15%, preferably about 0.001% to about 0.05%, fluoride by weightof the composition.

The compositions of this invention may be substantially solid or pastyin character such as dental cream, toothpaste toothpowder or chewinggum. Solid or pasty oral compositions contain polishing materials.Typical polishing materials are abrasive particulate materials havingparticle sizes of up to about 20 microns. Nonlimiting illustrativeexamples include: water-insoluble sodium metaphosphate, potassiummetaphosphate, tricalcium phosphate, dihydrated calcium phosphate,anhydrous dicalcium phosphate, dicalcium phosphate, calciumpyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calciumcarbonate, alumina, aluminum silicate, zirconium silicates, silica,bentonite, and mixtures thereof. Polishing materials are generallypresent in an amount from about 20% to about 99% by weight of thecomposition. Preferably, it is present in amounts from about 20% toabout 75% in toothpaste, and from about 70% to about 99% in toothpowder.

In clear gels, a polishing agent of colloidal silica and alkali metalaluminosilicate complexes are preferred since they have refractiveindices close to the refractive indices of gelling agent liquid systemscommonly used in dentifrices.

The compositions of the present invention may additionally containsweeteners, flavorants and colorants.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist:

A. Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, dextrose, sucrose, maltose, partiallyhydrolyzed starch, or corn syrup solids and sugar alcohols such assorbitol, xylitol, mannitol and mixtures thereof.

B. Water-soluble artificial sweeteners such as the soluble saccharinsalts, i.e., sodium, or calcium saccharin salts, cyclamate salts,acesulfame-K and the like, and the free acid form of saccharin.

C. Dipeptide based sweeteners such as L-phenylalanine methyl ester andmaterials described in U.S. Pat. No. 3,492,131 and the like.

In general, the amount of sweetener will vary with the desired amount ofsweetness selected for a particular composition. This amount willnormally be 0.01% to about 40% by weight. The water-soluble sweetenersdescribed in category A above, are preferably used in amounts of about5% to about 40% by weight, and most preferably from about 10% to about20% by weight of the final composition. In contrast, the artificialsweeteners described in categories B and C are used in amount of about0.005% to about 5.0% and most preferably about 0.05% to about 2.5% byweight of the final composition. These amounts are ordinarily necessaryto achieve a desired level of sweetness independent from the flavorlevel achieved from flavorants.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, citrus flavors such as orange and lemon,artificial vanilla, cinnamon, various fruit flavors and the like. Bothindividual and mixed flavors are contemplated. The flavorings aregenerally utilized in amounts that will vary depending upon theindividual flavor, and may, for example range in amounts of about 0.1%to about 6% by weight of the final composition.

The colorants useful in the present invention, include the pigmentswhich may be incorporated in amounts of up to about 2% by weight of thecomposition. Also, the colorants may include other dyes suitable forfood, drug and cosmetic applications, and known as F.D. & C. dyes andthe like. The materials acceptable for the foregoing spectrum of use arepreferably water-soluble. Illustrative examples include the indigo dye,known as F.D. & C. Blue No. 2, which is the disodium salt of5,5-indigotindisulfonic acid. Similarly, the dye known as F.D. & C.Green No. 1, comprises a triphenylmethane dye and is the monosodium saltof 4-[4-N-ethyl-p -sulfobenzylamino) diphenylmethylene]- [1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine]. A full recitation of allF.D. & C. and D. & C. colorants useful in the present invention andtheir corresponding chemical structures may be found in the Kirk-OthmerEncyclopedia of Chemical Technology, 3rd Edition, in Volume 6, at pages561-595, which text is accordingly incorporated herein by reference.

The present invention also involves a method for treating teeth and gumsto reduce plaque or gingivitis comprising applying to the surface of theteeth and/or gums the compositions of this invention as describedearlier. The compositions can be applied to the teeth and gums by anyconventional means such as brushing, spraying, painting or rinsing ofthe oral cavity and the like. The compositions not only retain plaqueaccumulation, but has been demonstrated to remove pre-existing plaque aswell. Additionally, the compositions show a prolonged effect on plaqueaccumulation following cessation of treatment through about one weekafter use. The compositions are also useful as a topical antiseptic anddisinfectant which is applied externally to the skin.

The following examples are presented to further illustrate thisinvention. The examples are intended in an illustrative sense and not ina limitative sense. All parts and percentages are on a weight basisunless otherwise indicated.

EXAMPLE I

A composition within the scope of this invention was prepared by mixingthe ingredients presented in Table I below. This composition was usefulas a mouthwash.

                  TABLE I                                                         ______________________________________                                        Ingredient          Amount (% w/v)                                            ______________________________________                                        3-(4-propylheptyl)-4-(2-hydroxyethyl)                                                             0.05                                                      morpholine hydrochloride                                                      Ethylenediaminetetraacetic acid                                                                   0.20                                                      Non-ionic Surfactant                                                                              0.70                                                      Sorbitol Solution (70% solids)                                                                    50.0                                                      Ethanol (95% in water)                                                                            10.0                                                      Coloring Agent      0.0004                                                    Flavoring Agent     0.15                                                      Deionized water     (quantity sufficient                                                          to 100%)                                                  ______________________________________                                    

EXAMPLE II

A composition within the scope of this invention was prepared by mixingthe ingredients presented in Table II below. This composition was usefulas an oral spray.

                  TABLE II                                                        ______________________________________                                        Ingredient          Amount (% w/v)                                            ______________________________________                                        3-(4-propylheptyl)-4-(2-hydroxyethyl)                                                             0.20                                                      morpholine hydrochloride                                                      Ethylenediaminetetraacetic acid                                                                   0.10                                                      Non-ionic Surfactant                                                                              1.20                                                      Citric acid, hydrous                                                                              0.07                                                      Ethanol (95% in water)                                                                            12.0                                                      Glycerol            20.0                                                      Sweeting Agent      0.01                                                      Flavoring Agent     0.10                                                      Deionized water     (quantity sufficient                                                          to 100%)                                                  ______________________________________                                    

The composition of Example II was tested against the bacteriaFusobacterium nucleatum (ATCC # 10953) by treating the bacteria with thecomposition for 30 minutes at 37° C. Transmission electron micrographsof the treated bacteria (FIG. 3) were taken and compared to themicrographs of 1) control bacteria cells in 0.1M phosphate-bufferedsaline solution at pH 7.0 (FIG. 1) and 2) bacteria cells (FIG. 2)treated with an aqueous composition containing only 0.2% of themorpholinoamino alcohol hydrochloride of Example II. The bacteria cellstreated with the composition of Example II according to this inventionshowed greater cell membrane destruction.

EXAMPLE III

Compositions within the scope of this invention were prepared by mixingthe ingredients presented in Table III below. These compositions wereuseful as a dentifrice.

                  TABLE III                                                       ______________________________________                                        Ingredient          Amount (% w/v)                                            ______________________________________                                        3-(4-propylheptyl)-4-(2-hydroxyethyl)                                                             0.20                                                      morpholine hydrochloride                                                      Ethylenediaminetetraacetic acid                                                                   0.20                                                      Sodium Fluoride     0.24                                                      Hydrated silica     10-50                                                     Xylitol             10-40                                                     Xanthan Gum         0.1-1.5                                                   Cocobetaine         0.1-1.5                                                   Flavoring Agent     0.9                                                       Deionized water     (quantity sufficient                                                          to 100%)                                                  ______________________________________                                    

EXAMPLE IV

A gel composition within the scope of this invention was prepared bymixing the ingredients presented in Table IV below.

                  TABLE IV                                                        ______________________________________                                        Ingredient          Amount (% w/v)                                            ______________________________________                                        3-(4-propylheptyl)-4-(2-hydroxyethyl)                                                             0.30                                                      morpholine hydrochloride                                                      Ethylenediaminetetraacetic acid                                                                   0.20                                                      Methyl Cellulose    2.0                                                       Sorbitol Solution (70% solids)                                                                    50.0                                                      Flavoring Agent     0.20                                                      Deionized water     (quantity sufficient                                                          to 100%)                                                  ______________________________________                                    

We claim:
 1. A composition having synergistic anti-plaque oranti-gingivitis activity comprising in combination a synergisticpharmaceutically effective amount of a) a morpholinoamino alcohol orpharmaceutically - acceptable salt thereof, wherein said morpholinoaminoalcohol has the chemical formula ##STR8## wherein R₁ is a straight orbranched alkyl group containing 8 to 16 carbon atoms at the 2- or3-position of the morpholino ring, and R₂ is a straight or branchedalkyl group containing 2 to 10 carbon atoms terminating with a hydroxygroup and (b) a chelating agent, wherein the amount of saidmorpholinoamino alcohol or salt thereof ranges from about 0.005% toabout 5% by weight, and the amount of said chelating agent ranges fromabout 0.03% to about 0.5% by weight based on total weight of saidcomposition.
 2. The composition of claim 1 wherein said chelating agentis selected from the group consisting of ethylenediaminetatraaceticacid, edetate sodium, edetate disodium, edetate trisodium, edetatecalcium disodium, deferoxamine, ditiocarb sodium, aluminum salts, citricacid-sodium salt, gluconic acid-sodium salt, tartaric acid, sodiumhexametaphosphate, anthranilic acid, phosphonate, polyacrylic acid,alkyl-diamine polyacetic acids and salts, penicillamine, pentetic acid,succimer and trientine.
 3. The composition of claim 1 wherein the sum ofthe carbon atoms in said groups R₁ and R₂ is 10 to
 20. 4. Thecomposition of claim 1 wherein said morpholinoamino alcohol is3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine.
 5. The composition ofclaim 1 wherein the amount of said morpholinoamino alcohol ranges fromabout 0.01% to about 1.0% by weight of said composition.
 6. Thecomposition of claim 1 wherein the amount of said chelating agent rangesfrom about 0.17% to about 0.40% by weight of said composition.
 7. Thecomposition of claim 1 wherein said pharmaceutically-acceptable saltsare the salts of acids selected from the group consisting of aceticacid, phosphoric acid, boric acid, hydrochloric acid, malic acid, oxalicacid, tartaric acid, succinic acid, gallic acid, beta- resorcylic acid,acetyl salicylic acid, salicylic acid, perchloric acid, barbituric acid,sulfanilic acid, phytic acid p-nitro benzoic acid, stearic acid,palmitic acid, oleic acid, myristic acid and lauric acid.
 8. Thecomposition of claim 1 wherein said composition is a tooth paste.
 9. Thecomposition of claim 1 wherein said composition is a liquid mouthwash.10. The composition of claim 1 wherein said composition is a chewinggum.
 11. The composition of claim 9 wherein said mouthwash compositioncomprises from 0 to about 30% by weight alcohol.
 12. The composition ofclaim 11 wherein said alcohol is ethanol.